Process for the preparation of intermediates useful in the preparation of pyranyl cyanoguanidine derivatives

ABSTRACT

A process for preparing compounds of the formula ##STR1## where a, b, c, R 1 , R 2 , and R 3  are as defined herein including the step of alkylating a phenol of formula ##STR2## with an acetylene of formula ##STR3## where X is chlorine; bromine; --OC(O)--R 5 , where R 5  is alkyl, aryl or substituted aryl; or --OCO 2  R 6 , where R 6  is alkyl or ##STR4## in the presence of a catalytic amount of a cuprous or cupric salt. The compounds of formula I are intermediates useful in the preparation of pyranyl cyanoguanidine derivatives.

REFERENCES TO OTHER APPLICATIONS

This application is a division of U.S. patent application Ser. No.08/128,436, filed Oct. 1, 1993, now U.S. Pat. No. 5,463,059, which is acontinuation-in-part of U.S. patent application Ser. No. 07/975,498,filed Nov. 10, 1992, now abandoned.

FIELD OF THE INVENTION

The present invention relates to novel processes for preparingintermediates useful in preparing compounds having potassium channelactivating activity.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to a novel process for preparingcompounds of the formula ##STR5## As used in formula I, and throughoutthe specification, the symbols have the following meanings:

a, b, and c are all carbon atoms or one of a, b and c is a nitrogen atomor --NO-- and the others are carbon atoms;

R₁ and R₂ are each independently hydrogen, alkyl or arylalkyl, or, R₁and R₂ taken together with the carbon atom to which they are attachedform a 5- to 7-membered carbocyclic ring;

R₃ is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,arylalkyl, cycloalkylalkyl, --CN, --NO₂, --COR, --COOR, --CONHR,--CONRR', --CF₃, S-alkyl, --SOalkyl, --SO₂ alkyl, ##STR6## halogen,amino, substituted amino, --OH, --O--alkyl, --OCF₃, --OCH₂ CF₃,--OCOalkyl, --OCONRalkyl, --NRCOalkyl, --NRCOOalkyl or --NRCONRR',wherein R and R' are independently hydrogen, alkyl, haloalkyl, aryl,arylalkyl, cycloalkyl, or (cycloalkyl)alkyl;

R₄ is hydrogen, alkyl, --OH, --O--alkyl, amino, substituted amino,--NHCOR, --CN, or --NO₂ ; and

n is an integer of 1 to 3.

Compounds of formula I may be prepared by alkylating a phenol of formula##STR7## with an acetylene of formula ##STR8## where X is chlorine;bromine; --OC(O)--R₅, where R₅ is alkyl, aryl or substituted aryl; or--OCO₂ R₆, where R₆ is alkyl or ##STR9## in the presence of a catalyticamount of a cuprous or cupric salt in an organic solvent and a base toform compounds of formula I.

DESCRIPTION OF THE INVENTION

The present invention relates to novel processes for preparing

compounds of formula I. Listed below are definitions of various termsused to describe the compounds of the instant invention. Thesedefinitions apply to the terms as they are used throughout thespecification (unless they are otherwise limited in specific instances)either individually or as part of a larger group.

The term "alkyl" refers to straight and branched chain hydrocarbons,containing 1 to 8 carbons in the normal chain, preferably 1 to 5 carbonssuch as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, 4,4-dimethyl-pentyl, 2,2,4-trimethylpentyl, the various branchedchain isomers thereof, and the like as well as such groups including ahalo-substituent, such as F, Br, Cl or I such as CCl₃ or CF₃, an alkoxysubstituent, an aryl substituent, an alkyl-aryl substituent, a haloarylsubstituent, a cycloalkyl substituent, an alkyl-cycloalkyl substituent,a hydroxy substituent, an alkylamino substituent, an alkanoylaminosubstituent, an arylcarbonylamino substituent, a nitro substituent, acyano substituent, a thiol substituent or an alkylthio substituent.

The terms "alkoxy" and "alkylthio" refer to such alkyl groups asdescribed above linked to an oxygen atom or sulfur atom respectively.

The term "alkenyl" refers to such groups as described above for alkyl,further containing at least one carbon to carbon double bond.

The term "alkynyl" refers to such groups as described above for alkyl,further containing at least one carbon to carbon triple bond.

The term "cycloalkyl" as employed herein includes saturated cyclichydrocarbon groups containing 3 to 7 ring carbons with cyclopropyl,cyclopentyl and cyclohexyl being preferred.

The term "halogen" or "halo" refers to chlorine, bromine, iodine andfluorine.

The term "aryl" refers to phenyl, 1-naphthyl, 2-naphthyl or monosubstituted phenyl, 1-naphthyl, 2-naphthyl wherein said substituents isalkyl of 1 to 4 carbons, alkylthio of 1 to 4 carbons, alkoxy of 1 to 4carbons, halo, nitro, cyano, hydroxy, amino, --NH--alkyl wherein alkylis of 1 to 4 carbons, --N(alkyl)₂ wherein alkyl is of 1 to 4 carbons,--CF₃, --OCH₂, ##STR10## (where R₁₃ is hydrogen, alkyl of 1 to 4carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, halo,hydroxy or --CF₃), --O--CH₂ -cycloalkyl, or --S--CH₂ -cycloalkyl, andall-substituted phenyl, 1-naphthyl, 2-naphthyl wherein said substituentsare selected from methyl, methoxy, methylthio, halo, --CF₃, nitro,amino, and --OCHF₂. Preferred aryl groups include unsubstituted phenyland monosubstituted or disubstituted phenyl wherein the substituent isnitro, halo, --CF₃, alkyl, cyano or methoxy.

The terms "heterocyclo" or "hetero" refer to fully saturated orunsaturated rings of 5 or 6 atoms containing one or two O and S atomsand/or one to four N atoms provided that the total number of heteroatoms in the ring is 4 or less. The hetero ring is attached by way of anavailable carbon atom. Preferred monocyclic hetero groups include 2- and3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl, and imidazolyl. Theterm hetero also includes bicyclic rings wherein the five or sixmembered ring containing O, S and N atoms as defined above is fused to abenzene ring and the bicyclic ring is attached by way of an availablecarbon atom. Preferred bicyclic hetero groups include 4, 5, 6, or7-indolyl, 4, 5, 6 or 7-isoindolyl, 5, 6, 7 or 8-quinolinyl, 5, 6, 7 or8-isoquinolinyl, 4, 5, 6, or 7-benzothiazolyl, 4, 5, 6 or 7-benzoxazolyl, 4, 5, 6 or 7-benzimidazolyl, 4, 5, 6 or 7-benzoxadiazolyland 4, 5, 6 or 7-benzofuranzanyl.

The terms "heterocyclo" or "hetero" also include such monocyclic andbicyclic rings wherein an available carbon atom is substituted with alower alkyl of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, loweralkoxy of 1 to 4 carbons, halo, nitro, keto, cyano, hydroxy, amino,--NH--alkyl wherein alkyl is of 1 to 4 carbons, --N(alkyl)₂ whereinalkyl is of 1 to 4 carbons, --CF₃, or --OCHF₂ or such monocyclic andbicyclic rings wherein two or three available carbons have substituentsselected from methyl, methoxy, methylthio, halo, --CF₃, nitro, hydroxy,amino and --OCHF₂.

The term "substituted amino" refers to a group of the formula --NZ₁ Z₂wherein Z₁ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl,cycloalkylalkyl and Z₂ is alkyl, cycloalkyl, aryl, arylalkyl,cycloalkylalkyl or Z₁ and Z₂ taken together with the nitrogen atom towhich they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl or 1-azepinyl substituted with alkyl, alkoxy, alkylthio,halo, trifluoromethyl or hydroxy.

Compounds of formula I may be prepared by alkylating a phenol of formula##STR11## with an acetylene of formula ##STR12## where X is chlorine;bromine; --OC(O)--R₅, where R₅ is alkyl, aryl or substituted aryl; or--OCO₂ R₆, where R₆ is alkyl or ##STR13## in the presence of a catalyticamount of a cuprous salt (such as cuprous chloride) or a cupric salt(such as cupric acetate monohydrate, cupric bromide, cupric chloridedihydrate, cupric methoxide, cupric trifluoro-methanesulfonate, cupricacetylacetonate, cupric hexafluoroacetylacetonate, cuprictetramethylheptanedionate and cupric trifluoroacetylacetonate) in anorganic solvent such as acetonitrile and a base such as1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo-[4.3.0]non-5-ene (DBN), or triethylamine, or othertrialkylamines to form compounds of formula I.

In preparing compounds of formula I as described above, it may benecessary to protect any amine, hydroxy or thiol groups during thereaction with protecting groups as known in the art.

Compounds of formula II are commercially available or are readilyprepared by methods known in the art.

Compounds of formula III may be prepared by methods disclosed in theliterature. For example, compounds of formula III where X is chlorineand R₁ and R₂ are methyl may be prepared as disclosed in G. F. Hennion,et al., J. Am. Chem. Soc., 72, 3542-3545 (1950) and G. F. Hennion etal., J. Org. Chem., 25, 725-727 (1961).

Compounds of formula III where X is bromine and R₁ and R₂ are methyl maybe prepared as disclosed in T. L. Jacobs et at., J. Org. Chem., 28, 1360(1963). Compounds of formula III where X is --OC(O)--R₅, where R₅ isalkyl, aryl or substituted aryl, may be prepared as described in G.Hofle et al., Synthesis, 619 (1972). Alternatively, compounds of formulaIII where X is --OC(O)--R₅, where R₅ is a substituted alkyl such as CCl₃or CF₃ may be prepared by treating compounds of formula IIIa ##STR14##with trichloroacetyl chloride, trifluoroacetic anhydride ortrichloroacetic anhydride in the presence of a base such astriethylamine or DBU. Compounds of formula IIIa are either commerciallyavailable or known in the art.

Compounds of formula III where X is --OCO₂ R₆, where R₆ is alkyl or##STR15## may be prepared as disclosed in J. Tsuji et at., J.Organometallic Chemistry, 417, 305-311 (1991) and U.S. Pat. No.3,348,939 to Delta W. Gier. The above cited references are incorporatedby reference herein.

Preferred compounds of formula Ill are those where X is chlorine;--OC(O)--R₅, where R₅ is substituted alkyl, most preferablytrifluoromethyl; or --OCO₂ R₆, where R₆ is methyl or ethyl.

It is also within the scope of this invention that compounds of formulaIII where X is trifluoroacetate or trichloroacetate may be formed insitu and reacted with compounds of formula II to produce the compoundsof formula I.

Compounds of formula I are key intermediates in the preparation ofpyranyl cyanoguanidine derivatives of the formula ##STR16## were a, b,c, R₁, R₂, R₃, and R₄ are as defined for formula I and ##STR17## R₈ ishydrogen, hydroxy, or --OC(O)--CH₃ ; R₉ and R₁₀ are independentlyhydrogen, alkyl, alkenyl, aryl, (heterocyclo)alkyl, heterocyclo,arylalkyl, cycloalkyl, (cycloalkyl)alkyl or substituted alkyl; or thesegroups optionally substituted with alkoxy, alkylthio or substitutedamino; or R₉ and R₁₀ taken together with the nitrogen atom to which theyare attached form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorphilinyl, 1-piperazinyl, 4-alkyl-1-piperazinylor 4-arylalkyl-1-piperazinyl, wherein each of the so-formed groups areoptionally substituted with alkyl, alkoxy, alkylthio, halogen ortrifluoromethyl; and

R₁₁ and R₁₂ are independently hydrogen, alkyl, alkenyl, aryl, arylalkyl,cycloalkyl or cycloalkylalkyl; or R₁₁ is as defined above and R₁₂ is anaryl group fused to 2 carbon atoms of the cyanoguanidine ring portion.

Compounds of formula IV and methods of preparing such compounds aredisclosed in U.S. Pat. No. 5,140,031, the disclosure of which isincorporated by reference herein.

Preferred compounds of formula IV are those where R₇ is ##STR18## and R₉is mono- or di-substituted phenyl.

An exemplary method of preparing the compounds of formula IV where R₇ is##STR19## using the intermediates of formula I, prepared as disclosedherein includes cyclizing compounds of formula I utilizing heat as knownin the art to form compounds of formula ##STR20## Compounds of formula Vare then convened to compounds of formula ##STR21## Compounds of formulaVI are then reacted with a thiourea of formula ##STR22## to obtain thecompounds of formula IV where R₇ is ##STR23## Other compounds of formulaIV may be prepared as disclosed in U.S. Pat. No. 5,140,301.

The thiourea of formula VII, wherein R₁₀ is hydrogen can be prepared byheating an isothiocyanate of the formula VIII

    R.sub.9 N═C═S

with either monosodium cyanamide or with cyanamide in the presence of anorganic base, such as triethylamine.

The other thioureas of formula VII can be prepared by standard methodsdescribed in the literature, such as by C. R. Rasmussen, et al.,Synthesis, p. 456 (1988); and V. V. Mozolis et al., Russian ChemicalReviews, 42, 587 (1973).

The following examples and preparations describe the manner and processof making and using the preferred embodiments of the invention and areillustrative rather than limiting. It should be understood that theremay be other embodiments which fall within the spirit and scope of theinvention as defined by the claims appended hereto.

Example 1 4-[(1,1-Dimethyl-2-propynyl)oxy]benzonitrile

A solution of cuprous chloride in acetonitrile was prepared immediatelybefore use. In a 10 mL volumetric flask was placed cuprous chloride(25.56 mg, 0.2582 mmol) and 10 mL of anhydrous acetonitrile.

To a solution of 4-cyanophenol (9.0 g, 75.55 mmol, commerciallyavailable) and anhydrous acetonitrile (120 mL) at ˜0° C. under argon wasadded 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 14.0 mL, 93.61 mmol,1.24 eq based on the input of 4-cyanophenol). A temperature increase to12.6° C. was observed. After the solution had cooled to 0° C., copperbronze (cooper powder, 49.8 mg, 0.783 mmol, 0.0104 eq, 1.04 mol %) wasadded followed by the addition of a portion of the cuprous chloride inacetonitrile solution prepared above (600 μL, 15.49 μmole, 0.000205 eq.,0.0205 mol %). To the resulting mixture was added, dropwise over 12minutes, 3-chloro-3-methyl-1-butyne (7.03 g, 68.54 mmol, 0.907 eq. basedon the input of 4-cyanophenol). The resulting mixture was allowed tostir at 0° C. under argon. After stirring for 10 hours, the reactionmixture was filtered through a small pad of Celite (to remove theremaining copper bronze) using additional acetonitrile to complete thetransfer and to wash the filter bed. The filtrate was concentrated atreduced pressure (bath temperature 40° C.) and the residue waspartitioned between 1N HCl (100 mL) and toluene (400 mL). The organicfraction was washed with 1N HCl (2×60 mL), 1N NaOH (2×60 mL), and brine.After drying (magnesium sulfate), the solvent was removed at reducedpressure to give crude title compound as a pale yellow oil (10.68 g).Distillation of the crude material (bulb-to-bulb, ˜70°-90° C., ˜0.15 mmHg) afforded the title compound as a colorless, low melting (mp 28°-29°C.) solid (10.40 g).

Elemental Analysis for C₁₂ H₁₁ NO:

Calcd: C, 77.81; H, 5.99; N, 7.56;

Found: C, 77.76; H, 6.02; N, 7.41.

Example 2 4-[(1,1-Dimethyl-2-propynyl)oxy]benzonitrile

To a solution of 4-cyanophenol (655 g, 5.50 mol) in acetonitrile (10 L)at 0° C. under nitrogen was added cuprous chloride (495 mg, 5 mmol,0.001 eq., 0.1 mol %). DBU (970 mL 6.51 mol) was added slowly whilemaintaining the temperature at <5° C. 3-Chloro-3-methyl-1-butyne (570mL, 5 mole) was added. After stirring for 4 hours at 0° C., the mixturewas concentrated at reduced pressure and the residue was partitionedbetween ethyl acetate (5 L) and 1N HCl (2 L). The organic fraction waswashed with 1N NaOH (2×1 L), water (1 L), and brine (1 L). After drying(magnesium sulfate), the solvent was removed at reduced pressure toafford the title compound as a yellow oil (930 g) which was used withoutfurther purification.

Example 3 4-[(1,1-Dimethyl-2 -propynyl)oxy]benzonitrile

To a solution of 4-cyanophenol (3.0 g, 25.18 mmol) and methyl1,1-dimethyl-2-propynyl carbonate (3.93 g, 27.64 mmol) in acetonitrile(24 mL) at 0° C. under argon was added DBU (5.0 mL, 33.43 mmol). To theresulting solution at 0° C. was added cuprous chloride (7.47 mg, 0.003eq., 0.3 mol %) and copper bronze (83 mg). After stirring at 0° C. for23 hours, the reaction mixture was filtered and the filtrate was dilutedwith toluene (˜400 mL). The resulting solution was washed with 1N HCl(×2), 1N NaOH (×2), and brine. After drying (magnesium sulfate), thesolvent was removed at reduced pressure to give crude title compound asa pale yellow oil (4.18 g). Distillation of the crude material(bulb-to-bulb) afforded the title compound as a colorless, low melting(mp 28°-29° C.) solid (4.02 g).

Example 4 Trichloroacetic acid 1,1 dimethyl 2-propynyl ester

2-Methyl-3-butyn-2-ol was added to n-butyllithium in THF at -30° C. andthe mixture gradually warmed to 5° C. After stirring 5 minutes, themixture was recooled to -30° C. and trichloroacetyl chloride was added.At 5° C., a precipitate began to form. The reaction was stirred for 5hours and checked by NMR. The alcohol was consumed. Hexane was added tothe mixture and the salts removed by filtration to give a clearsolution. The solvents were removed under vacuum to give a clearslightly yellow oil. The yield was 66.0% and analysis (gaschromatography) indicated a homogeneity index of 86%.

Alternate Procedures

1. 4-Dimethylamino pyridine (DMAP)/triethylamine was used in place ofn-butyllithium in the above procedure. Trichloroacetyl chloride wasadded to the 2-methyl-3-butyn-2-ol, triethylamine and DMAP at 0° to 5°C. After warming to 22° C., the reaction was 66% complete. Stirring foran additional hour did not increase the conversion. Therefore, 0.5 eq.of triethylamine and trichloroacetyl chloride were added and stirred for16 hours. The 2-methyl-3-butyn-2-ol was entirely consumed. The reactionmixture was diluted with hexane and washed with water, 1N HCl, saturatedsodium bicarbonate and brine. After drying over anhydrous magnesiumsulfate, the solvent was removed under vacuum. The yield was 75.5% andanalysis (gas chromatography) indicated a homogeneity index of 94%.

2. The above alternative reaction was run at twice the concentration andwith an additional 0.5 eq. of triethylamine and trichloroacetylchloride. The reaction was complete after 1 hour at 0° to 5° C. asindicated by the absence of 2-methyl-3-butyn-2-ol by GC analysis. Afterstirring the reaction at 22° C. for 2.5 days, the GCHI of the productwas unchanged. The reaction was worked up as described above and 60.4 gof product was isolated in a 87.8% yield and analysis (gaschromatography) indicated a homogeneity index of 88%.

Example 5 4-[(1,1-Dimethyl-2-propynyl)oxy]benzonitrile

2-Methyl-3-butyn-2-ol (56.4 mL, 0.58 mol) was dissolved in acetonitrile(300 mL) and was cooled to 0° C. under nitrogen. DBU (112 mL, 0.75 mol)was then added over a period of 15 minutes with the temperature notexceeding 0° C. After stirring 5 minutes, trifluoroacetic anhydride(82.0 mL, 0.58 mol) was added slowly during a 45 minute period whilemaintaining the temperature at less than 2° C.

4-Hydroxybenzonitrile (60.0 g, 0.50 mol) and cuprous chloride (0.05 g,0.1 mol %) were dissolved in acetonitrile (300 mL) at 22° C. Thissolution was then cooled to 0° C. under nitrogen. DBU (97.1 mL, 0.65mol) was added over a period of 15 minutes between 0° and 5° C.

The preformed 2-methyl-3-butyn-2-ol ester solution was dripped into the4-hydroxybenzonitrile solution over 3 hours, keeping the temperaturebetween -2° C. and 0° C. After stirring 2 additional hours, theacetonitrile was removed under vacuum. The residue was dissolved inethyl acetate (750 mL) and washed with 1N sodium hydroxide (3×300 mLportions), 1N hydrochloric acid (3×300 mL portions), water (1×300 mLportion), and brine (1×300 mL). The organic layer was then dried overanhydrous magnesium sulfate and the solvent evaporated under reducedpressure yielding the title compound (82.9 g) as a low melting solid.Analysis (HPLC:high performance liquid chromatography) indicated ahomogeneity index of 97%.

Example 6 4-[(1,1-Dimethyl-2-propynyl)oxy]benzonitrile

To a solution of 4-cyanophenol (6.55 g, 55.0 mmol) in anhydrousacetonitrile (50 mL) at ˜0° C. under argon was added DBU (9.04 mL, 60.45mmol). After the solution had cooled to ˜0° C.,3-chloro-3-methyl-1-butyne (5.13 g, 50 mmol) was added followed bycupric chloride dihydrate (9.62 mg, 0.056 mmol). After stirring at ˜0°C. for 5 hours, the mixture was concentrated at reduced pressure. Theresidue was partitioned between 1N HCl (50 mL) and toluene (300 mL). Theorganic fraction was washed with 1N HCl (2×50 mL), 1N NaOH (2×50 mL),and brine. After drying (magnesium sulfate), the solvent was removed atreduced pressure to give crude title compound as a nearly colorless oil.Distillation of the crude material (bulb to bulb) afforded the titlecompound as a colorless, low melting solid (7.25 g).

Example 7 4-[(1,1-Dimethyl-2-pronynyl)oxy]benzonitrile

To a solution of 4-cyanophenol (6.55 g, 55.0 mmol) in anhydrousacetonitrile (50 mL) at ˜0° C. under argon was added DBU (9.90 mL, 6.2mmol). After the solution had cooled to ˜0° C.,3-chloro-3-methyl-1-butyne (7.10 g, 69.2 mmol) was added followed bycopper(II) acetylacetonate (87.4 mg, 0.33 mmol). After stirring at ˜0°C. for 7 hours, the mixture was concentrated at reduced pressure. Theresidue was partitioned between 1N HCl (70 mL) and toluene (300 mL). Theorganic fraction was washed with 1N HCl (2×60 mL), 1N NaOH (2×50 mL), 1NNaHCO₃, and brine. After drying (magnesium sulfate), the solvent wasremoved at reduced pressure to give crude title compound as a paleyellow oil. Distillation of the crude material (bulb to bulb) affordedthe title compound as a colorless, low melting solid (9.56 g).

Example 8 4-[(1,1-Dimethyl-2-propynyl)oxy]benzonitrile

To a solution of 4-cyanophenol (3.0 g, 25.18 mmol) and methyl1,1-dimethyl-2-propynyl carbonate (3.93 g, 27.64 mmol) in anhydrousacetonitrile (24 mL) at 0° C. under argon was added DBU (5.0 mL, 33.43mmol). After the solution had cooled to ˜0° C., cupric chloridedihydrate (14.6 mg, 0.086 mmol) was added. After stirring at ˜0° C. for23 hours, the mixture was concentrated at reduced pressure. The residuewas partitioned between 1N HCl (44 mL) and toluene (200 mL). The organicfraction was washed with 1N HCl (2×40 mL), 1N NaOH (2×40 mL), 1N NaHCO₃,and brine. After drying (magnesium sulfate), the solvent was removed atreduced pressure to give crude title compound as a pale yellow oil.Distillation of the crude material (bulb to bulb) afforded the titlecompound as a colorless, low melting solid (4.05 g).

Example 9 4-[(1,1-Dimethyl-2-propynyl)oxy]benzonitrile

To a solution of 4-cyanophenol (3.0 g, 25.18 mmol) and methyl1,1-dimethyl-2-propynyl carbonate (3.93 g, 27.64 mmol) in anhydrousacetonitrile (24 mL) at 0° C. under argon was added DBU (5.0 mL, 33.43mmol). After the solution had cooled to ˜0° C., copper(II)acetylacetonate (66.4 mg, 0.254 mmol) was added. After stirring at ˜0°C. for 72 hours. the mixture was concentrated at reduced pressure. Theresidue was partitioned between 1N HCl (40 mL) and toluene (200 mL). Theorganic fraction was washed with 1N HCl (2×40 mL), 1N NaOH (2×40 mL), 1NNaHCO₃, and brine. After drying (magnesium sulfate), the solvent wasremoved at reduced pressure to give crude title compound as a paleyellow oil. Distillation of the crude material (bulb to bulb) affordedthe title compound as a colorless, low melting solid (4.59 g).

Example 10 4-[(1,1-Dimethyl-2-propynyl)oxy]benzonitrile

To a solution of 2-methyl-3-butyn-2-ol (4.88 g, 58.0 mmol) in anhydrousacetonitrile (30 mL) under argon and cooled in an ice-salt bath (-5° C.)was added DBU (11.2 mL, 74.9 mmol). Trifluoroacetic anhydride (8.2 mL,58.0 mmol) was added during a 25 minute period while maintaining thetemperature at less than 2° C. The resulting 1,1-dimethyl-2propynyltrifluoroacetate solution was allowed to stir at ˜0° C. (ice bath) for30 minutes before addition to the 4-cyanophenol solution.

To a solution of 4-cyanophenol (6.0 g, 50.4 mmol) in anhydrousacetonitrile (30 mL) under argon and cooled in an ice-salt bath (-4° C.)was added DBU (9.7 mL, 64.9 mmol) and cupric chloride dihydrate (9.3 mg,0.055 mmol).

The 1,1-dimethyl-2-propynyl trifluoroacetate solution, maintained at 0°C., was added to the 4-cyanophenol solution over a 40 minute periodwhile keeping the temperature at ˜0° C. The resulting mixture wasstirred at ˜0° C. (ice bath). After stirring for 5 hours, the mixturewas concentrated at reduced pressure. The residue was partitionedbetween water (50 mL) and toluene (300 mL). The organic fraction waswashed with 1N HCl (3×50 mL), 1N NaOH (2×50 mL), 1N NaHCO₃, and brine.After drying (magnesium sulfate), the solvent was removed at reducedpressure to give crude title compound as a very pale yellow oil.Distillation of the crude material (bulb to bulb) afforded the titlecompound as a colorless, low melting solid (8.04 g).

Example 11 4-[(1,1-Dimethyl-2-propynyl)oxy]benzonitrile

To a solution of 2-methyl-3-butyn-2-ol (5.85 g, 69.5 mmol) in anhydrousacetonitrile (36 mL) under argon and cooled in an ice-salt bath (-5° C.)was added DBU (13.5 mL, 90.3 mmol). Trifluoroacetic anhydride (9.8 mL,69.4 mmol) was added during a 33 minute period while maintaining thetemperature at less than 2° C. The resulting 1,1-dimethyl-2propynyltrifluoroacetate solution was allowed to stir at ˜0° C. (ice bath) for30 minutes before addition to the 4-cyanophenol solution.

To a solution of 4-cyanophenol (6.0 g, 50.4 mmol) in anhydrousacetonitrile (30 mL) under argon and cooled in an ice-salt bath (-3° C.)was added DBU (9.7 mL, 64.9 mmol) and copper(II) acetylacetonate (78 mg,0.298 mmol).

The 1,1-dimethyl-2-propynyl trifluoroacetate solution, maintained at 0°C., was added to the 4-cyanophenol solution over a 35 minute periodwhile keeping the temperature at ˜0 ° C. The resulting mixture wasstirred at ˜0° C. (ice bath). After stirring for 90 minutes, water (10mL) was added and the resulting mixture was concentrated at reducedpressure. The residue was partitioned between water (50 mL) and toluene(300 mL). The organic fraction was washed with 1N HCl (3×50 mL), 1N NaOH(2×50 mL), 1N NaHCO₃, and brine. After drying (magnesium sulfate), thesolvent was removed at reduced pressure to give crude title compound asa yellow oil. Distillation of the crude material (bulb to bulb) affordedthe title compound as a colorless, low melting solid (8.93 g).

What is claimed is:
 1. A process for the preparation of compounds offormula ##STR24## where a, b, and c are all carbon atoms or one of a, band c is a nitrogen atom or --NO-- and the others are carbon atoms;R₁and R₂ are each independently hydrogen, alkyl or arylalkyl, or, R₁ andR₂ taken together with the carbon atom to which they are attached form a5- to 7-membered carbocyclic ring; R₃ is hydrogen, alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, arylalkyl, cycloalkylalkyl, --CN, --NO₂,--COR, --COOR, --CONHR, --CONRR', --CF₃, S-alkyl, --SOalkyl, --SO₂alkyl, ##STR25## halogen, amino, substituted amino, --OH, --O--alkyl,--OCF₃, --OCH₂ CF₃, --OCOalkyl, --OCONRalkyl, --NRCOalkyl, --NRCOOalkylor --NRCONRR', wherein R and R' are independently hydrogen, alkyl,haloalkyl, aryl, arylalkyl, cycloalkyl, or (cycloalkyl)alkyl; R₄ ishydrogen, alkyl, --OH, --O--alkyl, amino, substituted amino, --NHCOR,--CN, or --NO₂ ; R₇ is ##STR26## R₈ is hydrogen, hydroxy, or--OC(O)--CH₃ ; R₉ and R₁₀ are independently hydrogen, alkyl, alkenyl,aryl, (heterocyclo)alkyl, heterocyclo, arylalkyl, cycloalkyl,(cycloalkyl)alkyl or substituted alkyl; or these groups optionallysubstituted with alkoxy, alkylthio or substituted amino; or R₉ and R₁₀taken together with the nitrogen atom to which they are attached form1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,4-thiamorphilinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl or4-arylalkyl-1-piperazinyl, wherein each of the so-formed groups areoptionally substituted with alkyl, alkoxy, alkylthio, halogen ortrifluoromethyl; and R₁₁ and R₁₂ are independently hydrogen, alkyl,alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl; or R₁₁ is asdefined above and R₁₂ is an aryl group fused to 2 carbon atoms of thecyanoguanidine ring portion; and n is an integer of 1 to 3; comprisingthe steps of (A) preparing a compound of the formula I ##STR27##comprising the step of alkylating a phenol of formula ##STR28## with anacetylene of formula ##STR29## where X is chlorine; bromine;--OC(O)--R₅, where R₅ is alkyl, aryl or substituted aryl; or --OCO₂ R₆,where R₆ is alkyl or ##STR30## in the presence of a catalytic amount ofa cuprous or cupric salt; and (B) converting said compound of theformula I prepared in step (A) to said compound of formula IV.
 2. Theprocess as recited in claim 1 wherein a compound of the formula##STR31## where R₇ is ##STR32## and R₉ is mono- or di-substituted phenylis prepared.